噬菌体蛋白激活和抑制DSR2 NADase的结构基础-动脉网

The structural basis of the activation and inhibition of DSR2 NADase by phage proteins

Nature 等信源发布 2024-07-23 10:39

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AbstractDSR2, a Sir2 domain-containing protein, protects bacteria from phage infection by hydrolyzing NAD+. The enzymatic activity of DSR2 is triggered by the SPR phage tail tube protein (TTP), while suppressed by the SPbeta phage-encoded DSAD1 protein, enabling phages to evade the host defense. However, the molecular mechanisms of activation and inhibition of DSR2 remain elusive.

摘要DSR2是一种含有Sir2结构域的蛋白质，通过水解NAD+来保护细菌免受噬菌体感染。DSR2的酶活性由SPR噬菌体尾管蛋白（TTP）触发，而被SPbeta噬菌体编码的DSAD1蛋白抑制，使噬菌体能够逃避宿主防御。然而，激活和抑制DSR2的分子机制仍然难以捉摸。

Here, we report the cryo-EM structures of apo DSR2, DSR2-TTP-NAD+ and DSR2-DSAD1 complexes. DSR2 assembles into a head-to-head tetramer mediated by its Sir2 domain. The C-terminal helical regions of DSR2 constitute four partner-binding cavities with opened and closed conformation. Two TTP molecules bind to two of the four C-terminal cavities, inducing conformational change of Sir2 domain to activate DSR2.

在这里，我们报告了载脂蛋白DSR2，DSR2-TTP-NAD+和DSR2-DSAD1复合物的低温EM结构。DSR2组装成由其Sir2结构域介导的头对头四聚体。DSR2的C端螺旋区域构成四个具有开放和闭合构象的伴侣结合腔。两个TTP分子与四个C末端空腔中的两个结合，诱导Sir2结构域的构象变化以激活DSR2。

Furthermore, DSAD1 competes with the activator for binding to the C-terminal cavity of DSR2, effectively suppressing its enzymatic activity. Our results provide the mechanistic insights into the DSR2-mediated anti-phage defense system and DSAD1-dependent phage immune evasion..

此外，DSAD1与激活剂竞争结合DSR2的C端腔，有效抑制其酶活性。我们的研究结果为DSR2介导的抗噬菌体防御系统和DSAD1依赖性噬菌体免疫逃避提供了机制上的见解。。

IntroductionFacing frequent attacks by virus, bacteria and archaea have evolved hundreds of diverse anti-phage defense systems to protect from phage infection, including the well-known restriction-modification (RM), CRISPR-Cas and abortive infection systems1,2. The RM and CRISPR-Cas systems are employed to directly degrade invaded phage DNA, providing a robust defense mechanism against phage infections3.

引言面对病毒，细菌和古细菌的频繁攻击，已经进化出数百种不同的抗噬菌体防御系统来防止噬菌体感染，包括众所周知的限制性修饰（RM），CRISPR-Cas和流产感染系统1,2。RM和CRISPR-Cas系统用于直接降解入侵的噬菌体DNA，为噬菌体感染提供了强大的防御机制3。

In contrast, the abortive infection system triggers programmed cell death in infected bacterial cells, sacrificing themselves to prevent phage propagation and ensure the survival of the bacterial population4. Bioinformatic analyses and subsequent experimental verification recently discovered plenty of anti-phage systems employing the abortive infection to inhibit phage replication, such as CBASS, toxin-antitoxin, Thoeris, Pycsar and defense-associated sirtuin (DSR) systems1,5.To combat the multilayered bacterial immune systems, phages have developed to express anti-defense proteins6,7,8,9.

相反，流产感染系统会触发受感染细菌细胞中的程序性细胞死亡，牺牲自己以防止噬菌体繁殖并确保细菌种群的存活4。生物信息学分析和随后的实验验证最近发现了许多利用流产感染抑制噬菌体复制的抗噬菌体系统，如CBASS，毒素-抗毒素，Thoeris，Pycsar和防御相关的sirtuin（DSR）系统1,5。为了对抗多层细菌免疫系统，噬菌体已经发展为表达抗防御蛋白6,7,8,9。

The most studied phage anti-defense proteins are the anti-restriction proteins and the anti-CRISPRs. The anti-restriction proteins function via directly interacting with the restriction enzymes or masking the modification sites to cope with the RM system10,11. The mechanisms utilized by anti-CRISPRs to overcome host defense systems are diverse, encompassing the inhibition of nuclease activity, induction of non-specific DNA binding, prevention of target DNA binding, and various other strategies12.

研究最多的噬菌体抗防御蛋白是抗限制蛋白和抗CRISPRs。抗限制性蛋白通过与限制性内切酶直接相互作用或掩盖修饰位点来应对RM系统10,11。抗CRISPR用于克服宿主防御系统的机制是多种多样的，包括抑制核酸酶活性，诱导非特异性DNA结合，预防靶DNA结合以及各种其他策略12。

A recent study reported four distinct families of anti-defense proteins, including the anti-Gabija system protein Gad1 and Gad2, anti-Thoeris protein Tad2 and anti-Hachiman defense protein Had17. The additional phage anti-defense mechanisms need more effort to investigate.DSR2, a sirtuin (Sir.

最近的一项研究报道了四个不同的抗防御蛋白家族，包括抗Gabija系统蛋白Gad1和Gad2，抗Thoeris蛋白Tad2和抗Hachiman防御蛋白Had17。额外的噬菌体反防御机制需要更多的努力来调查。DSR2，一种sirtuin（先生）。

Data availability

数据可用性

The cryo-EM density maps generated in this study have been deposited in the Electron Microscopy Data Bank (EMDB) under accession code EMDB-38872 [https://www.emdataresource.org/EMD-38872] (DSR2 H171A (crosslinked) partial structure); EMDB-38824 [https://www.emdataresource.org/EMD-38824] (DSR2 H171A (crosslinked) apo structure); EMDB-39925 [https://www.emdataresource.org/EMD-39925] (DSR2-TTP-NAD+ complex); EMDB-38889 [https://www.emdataresource.org/EMD-38889] (DSR2-DSAD1 (crosslinked) partial complex); EMDB-38902 [https://www.emdataresource.org/EMD-38902] (DSR2-DSAD1 complex with two DSAD1 on the same side); EMDB-38907 [https://www.emdataresource.org/EMD-38907] (DSR2-DSAD1 with two DSAD1 on the opposite side).

本研究中产生的低温电磁密度图已保存在电子显微镜数据库（EMDB）中，登录号为EMDB-38872[https://www.emdataresource.org/EMD-38872]（DSR2 H171A（交联）部分结构）；EMDB-38824[https://www.emdataresource.org/EMD-38824]（DSR2 H171A（交联）载脂蛋白结构）；EMDB-39925[https://www.emdataresource.org/EMD-39925]；EMDB-38889[https://www.emdataresource.org/EMD-38889]（DSR2-DSAD1（交联）部分复合物）；EMDB-38902[https://www.emdataresource.org/EMD-38902]（DSR2-DSAD1复合物，同一侧有两个DSAD1）；EMDB-38907[https://www.emdataresource.org/EMD-38907]（DSR2-DSAD1，另一侧有两个DSAD1）。

The atomic coordinates have been deposited in the Protein Data Bank (PDB) with accession number 8Y34 [https://www.rcsb.org/structure/unreleased/8Y34] (DSR2 H171A (crosslinked) partial structure); 8Y13 [https://www.rcsb.org/structure/unreleased/8Y13] (DSR2 H171A (crosslinked) apo structure); 8ZC9 [https://www.rcsb.org/structure/unreleased/8ZC9] (DSR2-TTP-NAD+ complex); 8Y3M [https://www.rcsb.org/structure/unreleased/8Y3M] (DSR2-DSAD1 (crosslinked) partial complex); 8Y3W [https://www.rcsb.org/structure/unreleased/8Y3W] (DSR2-DSAD1 complex with two DSAD1 on the same side); 8Y3Y [https://www.rcsb.org/structure/unreleased/8Y3Y] (DSR2-DSAD1complex with two DSAD1 on the opposite side). Source data are provided with this paper..

原子坐标已保存在蛋白质数据库（PDB）中，登录号为8Y34[https://www.rcsb.org/structure/unreleased/8Y34]（DSR2 H171A（交联）部分结构）；8Y13型[https://www.rcsb.org/structure/unreleased/8Y13]（DSR2 H171A（交联）载脂蛋白结构）；8ZC9[https://www.rcsb.org/structure/unreleased/8ZC9]；8Y3M[https://www.rcsb.org/structure/unreleased/8Y3M]（DSR2-DSAD1（交联）部分复合物）；8Y3W[https://www.rcsb.org/structure/unreleased/8Y3W]（DSR2-DSAD1复合物，同一侧有两个DSAD1）；8Y3Y年[https://www.rcsb.org/structure/unreleased/8Y3Y]（DSR2-DSAD1复合物，另一侧有两个DSAD1）。本文提供了源数据。。

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Download referencesAcknowledgementsWe thank the staff at the Cryo-EM Facility of Westlake University for technical assistant. This work was supported in part by the National Natural Science Foundation of China (32370742 to F.L., 32271264 to Z.S., 32200129 to R.Y., 81901168 to L.Y.), Huxiang Young Talents Program (2022RC1163 to F.L.), Natural Science Foundation of Hunan Province (2022JJ20056 to F.L., 2023JJ40437 to R.Y., 2021JJ20075 to L.Y.), Natural Science Foundation of Changsha City (kq2202088 to F.L.) and the Westlake Education Foundation (to Z.S.).Author informationAuthor notesThese authors contributed equally: Ruiwen Wang, Qi Xu.Authors and AffiliationsMOE Key Laboratory of Rare Pediatric Diseases, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaRuiwen Wang, Zhuoxi Wu, Hao Guo, Tianzhui Liao, Ling Yuan & Faxiang LiZhejiang Key Laboratory of Structural Biology, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, ChinaQi Xu, Jialu Li, Yuan Shi, Haishan Gao & Zhubing ShiWestlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, ChinaQi Xu, Jialu Li, Yuan Shi, Haishan Gao & Zhubing ShiState Key Laboratory of Developmental Biology of Freshwater Fish, Engineering Research Center of Polyploid Fish Reproduction and Breeding of the State Education Ministry, College of Life Sciences, Hunan Normal University, Changsha, Hunan, ChinaRong YangAuthorsRuiwen WangView author publicationsYou can also search for this author in.

下载参考文献致谢我们感谢西湖大学低温电磁设施的工作人员提供技术援助。这项工作得到了国家自然科学基金（32370742至F.L.，32271264至Z.S.，32200129至R.Y.，81901168至L.Y.），湖湘青年人才计划（2022RC1163至F.L.），湖南省自然科学基金（2022JJ20056至F.L.，2023JJ40437至R.Y.，2021JJ20075至L.Y.），长沙市自然科学基金（kq2202088至F.L.）和西湖教育基金（至Z.S.）的部分支持。作者信息作者注意到这些作者做出了同样的贡献：王瑞文，齐旭。作者和单位中南大学生命科学学院医学遗传学中心罕见儿科疾病重点实验室，湖南长沙，王瑞文，吴卓喜，郭浩，廖天柱，廖凌远，李泽江西湖大学生命科学学院结构生物学重点实验室，浙江杭州，徐华琦，李嘉璐，袁石，海山高，朱炳石河子生命科学与生物医学实验室，浙江杭州，徐华琦，李嘉璐，袁石，海山高，朱炳石河子鱼发育生物学国家重点实验室，多倍体鱼繁殖工程研究中心国家教育部，湖南师范大学生命科学学院，湖南长沙，杨荣作者王瑞文作者出版物你也可以在中搜索这位作者。

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PubMed Google ScholarContributionsF.L., Z.S. and R.Y. conceived and supervised the project. R.W., Q.X., T.L., Z.W. and H.G. performed plasmids construction, protein purification, and biochemical analysis. Q.X., J.L. and Y.S. performed Cryo-EM grids preparation, data collection and structure data analysis.

PubMed谷歌学术贡献。五十、，Z.S.和R.Y.构思并监督了该项目。R、 W.，Q.X.，T。五十、，Z.W.和H.G.进行了质粒构建，蛋白质纯化和生化分析。Q、 X.，J.L.和Y.S.进行了低温电磁网格制备，数据收集和结构数据分析。

L.Y. participated in biochemical assay design and manuscript preparation. F.L., Z.S. and H.G. built the structural models and wrote the manuscript.Corresponding authorsCorrespondence to.

五十、 Y.参与了生化分析设计和手稿准备。F、 L.，Z.S.和H.G.建立了结构模型并撰写了手稿。通讯作者通讯。

Rong Yang, Zhubing Shi or Faxiang Li.Ethics declarations

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Nature Communications thanks Songying Ouyang, Malcolm White and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

《自然通讯》感谢宋莹（音译）欧阳（音译）、马尔科姆·怀特（音译）和另一位匿名审稿人（音译），感谢他们对这项工作的同行评议做出的贡献。可以获得同行评议文件。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationSupplementary informationSupplementary Movie 1Supplementary Movie 2Supplementary Movie 3Supplementary Data 1Description of Additional Supplementary FilesReporting SummaryPeer Review FileSource dataSource DataRights and permissions.

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Reprints and permissionsAbout this articleCite this articleWang, R., Xu, Q., Wu, Z. et al. The structural basis of the activation and inhibition of DSR2 NADase by phage proteins.

转载和许可本文引用本文Wang，R.，Xu，Q.，Wu，Z。等人。噬菌体蛋白激活和抑制DSR2 NADase的结构基础。

Nat Commun 15, 6185 (2024). https://doi.org/10.1038/s41467-024-50410-0Download citationReceived: 29 January 2024Accepted: 09 July 2024Published: 23 July 2024DOI: https://doi.org/10.1038/s41467-024-50410-0Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《国家公社》156185（2024）。https://doi.org/10.1038/s41467-024-50410-0Download引文接收日期：2024年1月29日接受日期：2024年7月9日发布日期：2024年7月23日OI：https://doi.org/10.1038/s41467-024-50410-0Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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